Acyclovir, 2-amino-1,9-dihydro-9-[(2-hydroxy-ethoxy)methyl]-6H-purin-6-one, is an antiviral agent that has been known for approximately twenty years. There are three principal acyclovir formulations that are commercially distributed: a tablet for oral administration, a cream formulation for topical administration, and a lyophilized powder for parenteral administration. Production of the lyophilized powder is expensive, requiring cost-intensive processes such as, for example, vacuum-freezing and specialized equipment such as, for example, condensers and lyophilization chambers. Additionally, the equipment must be operated under sterile conditions, further increasing the cost of the product. For medical applications, the lyophilized powder must be properly reconstituted immediately prior to parenteral administration to a patient in need thereof.
There are many problems associated with the reconstitution of acyclovir. The reconstitution of acyclovir, which is time consuming and labor intensive, must be carried out by a medical professional, resulting in the inefficient consumption of the medical professional's time. Further, reconstitution sometimes gives formulations with particulate matter, requiring the interpretation of the medical professional. Such labor and time burden with respect to the medical professional's time increases the overall cost of the treatment to the patient.
Further, due to human error and varying degrees of skill among medical professionals, there is an increased risk of contamination during the reconstitution process. If the reconstitution is not performed aseptically, there is an increased risk of contamination of the formulation by harmful pathogens such as, for example, bacteria. Such contamination can result in harm to the patient, who may already be in a medically compromised state. Even if the reconstitution is performed aseptically, there remains a risk that the reconstitution will not be performed properly, for example, if the medical professional uses the wrong diluent or the wrong quantity of diluent. If the wrong diluent is used, the entire formulation could be medically ineffective, and possibly harmful, to the patient. If the correct diluent is used, but in incorrect ratio with respect to the acyclovir sodium, problems with concentration and/or solubilty can occur. As a result, there is a risk of variability in the safety and efficacy of the reconstituted product.
Another problem with reconstitution is the increased potential for safety hazards to the medical professional. Since reconstitution of acyclovir typically involves spikes and/or needles and puncturing of the container septa therewith, the medical professional is exposed to an increased risk of receiving a needle/spike stick. Such hazards are not only detrimental to the safety of the medical profession, but also are further complicated by the administrative costs related to the reporting, tracking, and documentation of facts surrounding needle/spike sticks, as required by most medical facilities. As a result, there is an increase in the overall cost of treatment, which ultimately falls on the patient.
Since aqueous solutions which contain an appreciable concentration of acyclovir require high pH, standard glass container incompatibility precludes long term storage of such solutions in a ready-to-use formulation. The pH required to maintain an aqueous solution of acyclovir is typically greater than about 10-11, depending on the desired concentration of acyclovir, due to the enormously greater aqueous solubility of the salt of acyclovir relative to the virtually insoluble undissociated form. The pH of aqueous acyclovir sodium, a highly alkaline compound, necessarily increases with increasing concentration of acyclovir. Since there is a great difference in solubility between acyclovir sodium and undissociated acyclovir, lowering the pH of the formulation would not be desirable due to precipitation of the relatively insoluble undissociated acyclovir. Such precipitation would make the formulation unacceptable for parenteral administration.
The incompatibility of glass at high pH conditions is well known. When a highly alkaline solution comes in contact with glass, alkaline attack upon the glass (generally by hydroxide ion) occurs within a relatively short time, resulting in the extraction of ions and the dislodging of glass flakes from the surface, thereby contaminating the solution. Even small amounts of such ions or particulate matter in an aqueous pharmaceutical solution can render it unacceptable for parenteral administration. The shelf life of reconstituted aqueous acyclovir in glass vials is evident from the instructions which accompany the package inserts. For example, according to the package insert, lyophilized acyclovir sold under the trademark Zovirax.RTM. sterile powder (Burroughs Wellcome), which is reconstituted in glass vials, must be used within twelve hours after reconstitution.
Some plastics may exhibit incompatibility problems as well. While some plastics contain polymers which are resistant to alkaline conditions, many standard plastics often contain monomers, plasticizing agents, processing agents (e.g., lubricants) and other materials which are released when the plastic comes into contact with an alkaline solution.
In view of the foregoing problems, there is a need for a ready-to-use acyclovir formulation for parenteral administration which does not require reconstitution prior to the administration thereof. Further, there exists a need for a cost effective method of storing aqueous acyclovir sodium solutions that will result in prolonged shelf life, yet will not produce container or drug-related particulate matter. There also exists a need for a cost effective alkali stable pharmaceutical product which enables the long term storage of aqueous acyclovir sodium at high pH. The present invention provides such a method and product. These and other advantages of the present invention, as well as additional inventive features, will be apparent from the description of the preferred embodiments provided herein.